This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF), a set of findings termed chronic allograft nephropathy (CAN), causes most kidney allograft losses. Despite progress in immunosuppression, CAN remains the main clinical challenge for improving long-term graft survival rate. The sustained damage to the allograft does not represent a single entity, but the summated effects of tissue injury from several pathogenic insults and the kidney's healing response, modified by alloimmunity and immunosuppression. CAN is the end-result of a series of time-dependent insults to the transplanted kidney resulting in permanent damage and loss of nephrons. A major challenge in the future of kidney transplantation is to identify the distinct and identifiable causes of CAN, to understand the biology of the process, and to develop treatments through the discovery of causal mechanisms.